By William A. Haseltine

This story is part of a larger mosaic of stories on Post-Acute Sequelae of Covid-19 (PASC), also known as Long Covid. Read part one and two of this series.

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Comparing brain volume before and after individuals were exposed to SARS-CoV-2, this study documents … [+] GETTY IMAGES

Thanks to a new study from the UK we are now beginning to uncover the effects of SARS-CoV-2 infections in the brain. Comparing brain volume before and after individuals were exposed to SARS-CoV-2, this study documents significant cortical gray matter loss, equivalent to nearly 10 years of aging. Gweanaelle Douaud, the study’s first author and Professor at the University of Oxford, says that infected individuals display structural “differences over time above and beyond any potential baseline differences.” Most strikingly, individuals that experienced no or only mild symptoms with Covid-19 displayed specifically significant changes, but cortical damage seems to occur regardless of disease severity, age, or sex. The effect of vaccination status not yet been investigated. It may be years before the long-term consequences of these structural differences are fully understood.

Douaud et al had unique access to an extensive biomedical database, called the UK BioBank. The UK BioBank provided pre-pandemic brain scans from 785 individuals that were used as a baseline for normal size and structure relative to each participant. About three years later, in May 2021, the same population of participants returned for new brain scans. From the total cohort, 401 individuals were infected with Covid-19 between scans and the remaining served recruited as controls.

Between the first and second brain scans, individuals previously infected with Covid-19 experienced a 0.7% reduction in overall cortical gray matter on average, compared to the control group. To put that into perspective, people middle aged and beyond only lose 0.2% to 0.3% of volume per year.

Although it is clear that SARS-CoV-2 can damage the brain, how this damage occurs without directly infecting nerve cells remains a mystery. Current theories suggest there may be multiple factors contributing to these deficits. Structural abnormalities in the brain may in fact be secondary to infection occurring in other sites around the body, including the olfactory epithelium. Considering how close the nose is to the brain, this Oxford University Study considered whether losing the sense of smell may be linked to other neurological damage.

Loss of smell is a consistent clinical feature of Covid-19, with recent studies suggesting that 86% of individuals exposed to the virus may experience partial or complete loss of smell. A smaller percentage of people also develop additional neurological complications, including brain fog, fatigue, impaired cognitive function, and encephalography, characterized by impairments in brain structure and function. For some, these symptoms may continue to linger anywhere from a few months to more than a year after the initial infection. These effects, however, do not discriminate between mild and severe disease.

First, Douaud et al. found reduced gray matter in several regions associated with olfaction, consistent with symptoms of prolonged loss of smell. Individuals exposed to Covid-19 experienced the most significant neural damage to the primary olfactory cortex, or piriform cortex. This structure receives input directly from olfactory receptors that pass through the olfactory bulb, making it the first neural target for processing and perceiving odors. Reduced cortical thickness was also observed in a connected region called the orbitofrontal cortex. Illustrated in Figure 1, the orbitofrontal cortex (OFC) receives inputs from the primary olfactory cortex and is commonly referred to as the secondary olfactory cortex.

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Figure 1: Schematic view of the human olfactory system. The primary and secondary olfactory cortices … [+] FROM: “ A REVIEW ON THE NEURAL BASES OF EPISODIC ODOR MEMORY: FROM LABORATORY-BASED TO AUTOBIOGRAPHICAL APPROACHES” SAIVE ET AL. 2014.

Damage to these areas may be linked to loss of smell, but there is no evidence of causation. Instead, researchers speculate that the loss of volume to brain regions associated with olfaction may be partially attributed to widespread damage to the olfactory epithelium that disrupts neural pathways and impairs function. As with many other neural systems, pathways that are not being used over a long period of time cease to exist, a process neuroscientists often call “use it or lose it” that causes brain tissues to shrink.

Surprisingly, Douaud et al. also found additional abnormalities in regions not normally associated with the sense of smell. In particular, they observed reduced gray matter volume in some regions of the limbic system, involving several structures important for producing behavioral and emotional responses. The largest differences, ranging from 0.2% to 2% reductions, were seen in the left parahippocampal gyrus and the entorhinal cortex. These regions play an important role in the hippocampal memory system, so gray matter loss could signify future memory impairments. Structures are shown below in Figure 2 for reference.

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Figure 2: Illustration of the limbic system. The parahippocampal gyrus and hippocampus, which … [+] BRUCEBLAUS, WIKIPEDIA COMMONS

Are the differences seen in these limbic structures also linked to deficits in the olfactory system during Covid-19? Douaud et al. argues that the parahippocampal gyrus, the orbitofrontal cortex and other parts of the limbic system are in some way connected to the olfactory cortex. Since sensory inputs, including those for olfaction, are transmitted and integrated all over the brain to guide a range of behavioral responses, damage to the olfactory epithelium may also have disastrous consequences on regions of the brain not exclusively involved in olfaction. More likely, however, these and other changes in brain structure may be a consequence of a robust immune response occurring all around the brain, albeit the mechanisms underlying inflammation-induced brain damage remain unclear.

Additional exploratory analyses found gray matter loss in the amygdala, the insula which borders the temporal cortex, and the front-most portion of the cingulate gyrus, known as the anterior cingulate gyrus. Interestingly, all these regions play a role in emotion processing and regulation. More research is needed to determine whether deficits in these brain regions may be linked to mood disorders associated with long-haul Covid-19, including depression and anxiety.

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Figure 3:Reference locations for amygdala, anterior cingulate cortex, and insula. APOLLO MEDICINE 2020

It is important to note that not every individual infected with Covid-19 will experience a reduction in brain volume, while others will experience much greater losses. Those hospitalized with Covid-19, for example, had more widespread tissue damage and atrophy, compared to those not hospitalized for infection. Beyond hospitalized vs. non-hospitalized, there was limited data from this study showing how severity of infection may contribute to these effects.

Finally, Douaud et al. asked whether these structural changes in the cerebral cortex are linked to new neurological symptoms following Covid-19 infection. They did not find significant correlations between structural changes and the prevalence of new neurological symptoms. However, does not mean that these changes will not impact brain function. They did find infected participants had a greater decline in their ability to perform a complex task, compared with the non-infected participants.

For a vast majority of people, the regenerative properties of the olfactory bulb restores the sense of smell within a few weeks or months. What about the rest of the brain? Damage to brain cells cannot be reversed. When tissues die, cerebrospinal fluid and other biomolecules fill the excess space to maintain the integrity of the brain. Perhaps, this explains why neurological complications associated with long-haul Covid-19 show little improvement over time. Years of additional research are needed before the consequences of losing so much gray matter are fully understood. Identifying these changes now will help us to better support and treat what will be a growing class of people with cognitive impairments.

Although the loss of smell is often one of the first symptoms of Covid-19 preceding any respiratory complications, the hypothesis that the SARS-CoV-2 damages the brain when it infects cells in the olfactory epithelium remains heavily-debated. Researchers do seem confident that the virus does not directly infect brain cells. If the nose is a window to the brain, it may be time to develop new vaccines that aim to close it off from the SARS-CoV-2 virus.

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